The present disclosure is directed to prosthetic medical devices, in particular, prosthetic heart valves. More particularly, the present disclosure is directed to prosthetic heart valves formed from biological tissue, and to the treatment of such tissue to resist calcification.
Bioprosthetic tissue is often used in bioprosthetic devices or to repair damaged tissue in a patient. For example, it has become common practice to replace damaged or diseased native heart valves with bioprosthetic valves. The bioprosthetic valve, which is also generally known as a “tissue valve,” may be made with tissue of biological origin, such as tissue of porcine or bovine origin. Such valves are less likely to cause blood clotting and have improved hemodynamic properties compared to mechanical valves that may be made of metal or synthetic polymeric materials.
The most common cause for the failure of implanted bioprosthetic devices is in vivo calcification. The mechanism of calcification of bioprosthetic tissue is not fully understood. Calcification may be due to host factors, implant factors, and extraneous factors such as mechanical stress. Certain components within the bioprosthetic tissue, such as phospholipids, cholesterol, collagen and elastin, are known to be susceptible to calcification. They can become calcified following the implantation of bioprosthetic valves. The calcification can result in undesirable stiffening or degradation of the bioprosthesis, which leads to device failure.
Typically prior to implantation, the biological tissue is chemically cross-linked or fixed with agents such as glutaraldehyde or formaldehyde in order to prevent rejection when implanted into a recipient, to provide sterilization, and to help stabilize the proteins in the tissue, thereby making the tissue and the bioprosthetic device containing such tissue more durable to withstand prolonged use and millions of cycles of opening and closing under circulatory pressure without fatigue. Glutaraldehyde is the most commonly used fixative that can be applied at a physiological pH under aqueous conditions for preparing tissue for implantation. Unfortunately, glutaraldehyde is now known to promote in vivo calcification. The unstable glutaraldehyde creates potential calcium binding sites within the tissue that can lead to calcification.
Various techniques have been developed in the treatment of bioprosthetic tissue for mitigating in vivo calcification. One such attempt, disclosed in U.S. Pat. No. 5,002,566 to Carpentier et al., involves a pretreatment of glutaraldehyde-fixed bioprosthetic tissue with a calcification-inhibiting amount of ferric or stannic ions or a mixture thereof. The CARPENTIER-EDWARDS ThermaFix™ tissue process is an FDA-approved anti-calcification treatment of bioprosthetic tissue that reduces the calcium binding sites by a two-step process, with a first thermal treatment to remove up to 81 percent of the unstable glutaraldehyde and a second chemical treatment to remove 98 percent of the phospholipids. In U.S. Pat. No. 5,476,516, Seifter et al. disclose a method of treating aldehyde-fixed biological tissue with a liquid polyol to minimize in vivo calcification. The polyol is at least 60% in a solution, and preferably solvent-free. Levy et al., in U.S. Pat. No. 5,746,775, discloses a tissue anti-calcification process for a collagenous biomaterial in which the biomaterial is exposed to an alcohol to inhibit calcification. The biomaterial, preferably glutaraldehyde-pretreated, is subjected to an aqueous solution of 60% to 80% of a lower aliphatic alcohol, such as ethanol, for a period of at least 20 minutes, and preferably, 24 to 72 hours. The biomaterial is then rinsed, and stored in a glutaraldehyde solution or ethanol-glutaraldehyde solution. This process reduces the toxicity of glutaraldehyde, and removes 99 percent of the cholesterol and 94 percent of the phospholipids in bioprosthetic tissue, resulting in resistance to calcification in various preclinical models.
To prevent the transmission of disease-causing microorganisms to the device recipient, the tissue and the bioprosthetic device made therefrom should be sterile. The bioprosthetic device should be stored in a sterile and stable condition from manufacture until use. For example, bioprosthetic heart valves, including surgical and transcatheter heart valves, are typically sterilized and stored in an aldehyde solution (i.e., glutaraldehyde or formaldehyde) prior to use. These solutions help keep the tissue in a hydrated state and kill any microbes that may be attached to the tissue. However, both glutaraldehyde and formaldehyde are irritants and have some inherent level of toxicity. Glutaraldehyde is also known to contribute to in vivo calcification. A bioprosthetic device that is stored in such a solution therefore must be extensively rinsed to remove any residual aldehydes prior to implantation.
Attempts have been made to develop a bioprosthetic valve that is in a substantially “dry” form, substantially free of glutaraldehyde or formaldehyde, and ready for implantation with minimal preparation prior to surgery. Chen et al., in U.S. Pat. No. 6,534,004, disclose a process for dry storing bioprosthetic devices comprising a tissue component. The process includes treating the fixed tissue component with an aqueous solution comprising dimensional stabilizers such as polyhydric alcohols or their derivatives. Another strategy, described in U.S. Pat. No. 8,748,490 to Dove et al., is to dehydrate the bioprosthetic tissue in a glycerol/ethanol mixture. However, such dehydration processes do not provide the tissue with calcification resistance.
Bioprosthetic tissue in the “dry” form is usually sterilized with ethylene oxide, gamma irradiation, or electron beam irradiation. However, ethylene oxide sterilization requires the tissue to be exposed to increased temperatures and water vapor which may damage or rehydrate the tissue. Gamma irradiation is known to cause backbone scission and breakage of collagen fibrils, leading to decreased mechanical and biochemical functionality in the tissue. Electron beam irradiation will also cleave the collagen backbone and lead to deterioration of the tissue structure and reactivity. These types of damage during sterilization and/or storage may contribute to valve deterioration and structural failure.
Therefore, there is a continuing need to develop a method of preparing bioprosthetic tissue or a bioprosthetic device containing such tissue so as to minimize in vivo calcification and allow for sterilization and storage in a non-toxic environment without causing damage to the tissue.